Increasing evidence demonstrates a crucial role of the innate immune system in the host's response against viral infection. In particular, natural killer (NK) cells represent important early effector cells of the innate immune defense as they exert their function without prior sensitization. NK cells can lyse virally infected cells and participate in the regulation of innate and adaptive immune responses, raising them to multifunctional members of the first line of immune defense against viral infections1"3. Unlike other lymphocytes they lack specific antigen receptors, but eliminate target cells following the integration of complex signals from an arsenal of inhibitory and activating receptors upon ligation of several classical and non-classical major histocompatibility complexes (MHC) on the surface of target cells4. In addition, it has been recently shown that NK cells express functional Toll-like receptors (TLR), which allow them to recognize foreign material without the assistance of ARC5"7. In HIV-1 infection, NK cells are of central importance as they can combat the viral infection itself as well as opportunistic pathogens like fungi and protozoa. Recent data demonstrating a significant association between slower HIV-1 disease progression and the presence of a particular NK killer immunoglobuline-like receptor gene (KIR3DS1) together with a specific group of HLA-B Bw4 alleles (Bw4-80lle) further emphasize the potential importance of NK cell activity in controlling HIV-1 replication and delaying disease progression8. The overall objective of this proposal is to study the antiviral activity of NK cells and the impact of HIV-1 infection on NK cell function. The following specific aims will be addressed: 1. Analysis of the impact of acute and chronic HIV-1 infection on NK cell phenotype and function 2. Analysis of the modulation of NK cell function by Toll-like receptor co-stimulation 3. Analysis of the mechanisms that determine NK cell recognition of HIV-1 infected cells a. Impact of the KIR/HLA compound genotype on NK cell function b. Impact of the peptides presented by HLA on KIR-mediated recognition by NK cells